Alzheimer’s Disease

Memory loss is normal as you age. It’s normal to forget why you walked into a room, but then remember later. It’s also normal to forget names, and occasionally have a hard time finding a word. It’s not normal if you can’t do things that you used to be able to do or if you get lost in familiar places. It’s not normal when a person can’t have a conversation because they can’t find the words, or they use the wrong word (tongs instead of scissors). Alzheimer’s disease (AD) is a neurodegenerative disease that causes loss of memory and thinking skills, and eventually interferes with the ability to carry out simple tasks.

Lifetime risk of Alzheimer’s is alarmingly high for women (20% will develop it), and 2/3 of Americans with Alzheimer’s are women (Nebel et al., 2018). Are rates of Alzheimer’s higher in women only because we tend to live longer? Both sex and gender affect the outcomes of many diseases. We don’t know the answers to this question yet, but it is starting to be addressed (Snyder et al., 2016).

There are many places to go for information about Alzheimer’s—what it is, how to recognize it, and what current medical practice for management of patients consists of. Two good starting places are the not-for-profit Alzheimer’s Association https://www.alz.org/ and The Alzforum https://www.alzforum.org/. If you are looking for help, the bottom line is that there is currently no medically accepted way to prevent, treat, or cure the disease—medical practice focuses on management of symptoms. However, we do discuss below intriguing lifestyle approaches that may offer hope for delaying disease progression. We also discuss some of the many approaches being used in basic research and in clinical trials to try to prevent the disease.

Most Alzheimer’s cases are believed to be caused by a combination of genetic, lifestyle, and environmental factors. A small percentage of cases are exclusively genetic and aren’t affected by lifestyle (Strobel) https://www.alzforum.org/early-onset-familial-ad/overview/what-early-onset-familial-alzheimer-disease-efad. There appears to be more than one biological process that can go wrong in the brain in AD, meaning the cause of the disease may be variable from person to person. Think of heart disease- it can be caused by high blood pressure, high blood sugar, high blood cholesterol, or multiple other factors. People with low cholesterol can still get heart attacks because other factors can all lead to clogged arteries. AD may be similar—the defining features of amyloid beta accumulating in plaque and a protein called tau accumulating in tangles appear to have multiple causes. This complexity is why the treatment approaches discussed below are so multi-faceted and address as many aspects of brain health as possible (Alzheimer’s Association, 2017).

In addition to Alzheimer’s, there are other kinds of dementia and reasons for cognitive impairment. In addition to amyloid beta and tau accumulating in AD, dementia can result from a buildup of Lewy bodies or a protein called TDP-43. Blood vessels that are clogged may not be able to supply neurons with enough oxygen and fuel. A burst blood vessel, such as in a stoke or a transient ischemic attack (TIA), may leave parts of the brain without a blood supply. These factors can all cause death of neurons, and more than one of these pathologies is likely to be going on simultaneously (Power et al., 2018).

Alzheimer’s Disease

Memory loss is normal as you age. It’s normal to forget why you walked into a room, but then remember later. It’s also normal to forget names, and occasionally have a hard time finding a word. It’s not normal if you can’t do things that you used to be able to do or if you get lost in familiar places. It’s not normal when a person can’t have a conversation because they can’t find the words, or they use the wrong word (tongs instead of scissors). Alzheimer’s disease (AD) is a neurodegenerative disease that causes loss of memory and thinking skills, and eventually interferes with the ability to carry out simple tasks.

Lifetime risk of Alzheimer’s is alarmingly high for women (20% will develop it), and 2/3 of Americans with Alzheimer’s are women (Nebel et al., 2018). Are rates of Alzheimer’s higher in women only because we tend to live longer? Both sex and gender affect the outcomes of many diseases. We don’t know the answers to this question yet, but it is starting to be addressed (Snyder et al., 2016).

There are many places to go for information about Alzheimer’s—what it is, how to recognize it, and what current medical practice for management of patients consists of. Two good starting places are the not-for-profit Alzheimer’s Association https://www.alz.org/ and The Alzforum https://www.alzforum.org/. If you are looking for help, the bottom line is that there is currently no medically accepted way to prevent, treat, or cure the disease—medical practice focuses on management of symptoms. However, we do discuss below intriguing lifestyle approaches that may offer hope for delaying disease progression. We also discuss some of the many approaches being used in basic research and in clinical trials to try to prevent the disease.

Most Alzheimer’s cases are believed to be caused by a combination of genetic, lifestyle, and environmental factors. A small percentage of cases are exclusively genetic and aren’t affected by lifestyle (Strobel) https://www.alzforum.org/early-onset-familial-ad/overview/what-early-onset-familial-alzheimer-disease-efad. There appears to be more than one biological process that can go wrong in the brain in AD, meaning the cause of the disease may be variable from person to person. Think of heart disease- it can be caused by high blood pressure, high blood sugar, high blood cholesterol, or multiple other factors. People with low cholesterol can still get heart attacks because other factors can all lead to clogged arteries. AD may be similar—the defining features of amyloid beta accumulating in plaque and a protein called tau accumulating in tangles appear to have multiple causes. This complexity is why the treatment approaches discussed below are so multi-faceted and address as many aspects of brain health as possible (Alzheimer’s Association, 2017).

In addition to Alzheimer’s, there are other kinds of dementia and reasons for cognitive impairment. In addition to amyloid beta and tau accumulating in AD, dementia can result from a buildup of Lewy bodies or a protein called TDP-43. Blood vessels that are clogged may not be able to supply neurons with enough oxygen and fuel. A burst blood vessel, such as in a stoke or a transient ischemic attack (TIA), may leave parts of the brain without a blood supply. These factors can all cause death of neurons, and more than one of these pathologies is likely to be going on simultaneously (Power et al., 2018).

Do you have Alzheimer’s?

The way to diagnose Alzheimer’s with absolute certainty is through a brain autopsy and the finding of amyloid and tau buildup. This is impractical. Here are some alternatives (Livingston et al., 2017). Your physician will want to conduct cognitive tests to assess your memory and brain function. The MMSE (Mini-Mental State Exam), Addenbroke’s Cognitive Exam, and Montreal Cognitive Assessment are validated tests, whereas online tests you find may not be as accurate. They will also want to do tests to rule out other reasons for your symptoms, including stroke, cardiovascular disease, medications, and depression. CT and MRI imaging can rule out tumors or head trauma, and may reveal brain atrophy (yes, your brain shrinks), an indicator of Alzheimer’s. PET imaging provides valuable information about how well the brain is working, but is not covered by Medicare. It has been shown that PET scans frequently provide significant information leading to changes in treatment strategies, but it is not known if this really helps in the long run (Rabinovici et al., 2019) (Khosravi et al., 2019). Some information can be gained by measuring the amount of amyloid and tau in spinal fluid https://www.nia.nih.gov/health/biomarkers-dementia-detection-and-research#other. These are all complex, expensive, invasive tests that are not routinely carried out without good cause. It should not be too long before a reliable blood test for amyloid beta is available commercially that will make diagnosis much simpler (Nakamura et al., 2018) (Schindler et al., 2019).

Clues in your genes

It’s debated in medical circles just how useful the currently imperfect genetic testing is, but rapid advances are being made that seem worth keeping up with. Rare mutations in the APP or presenilin 1 genes always lead to disease, and a mutation in presenilin 2 is 95% predictive of AD (Alzheimer’s Association, 2017), so if you have AD symptoms in middle age and have a family history, your neurologist may order a presenilin gene test. Which tests are commercially available vs. available only as a part of a research project is continually changing in this fast-moving field https://www.alzforum.org/early-onset-familial-ad/diagnosisgenetics/genetic-testing-and-counseling-early-onset-familial). Information about your risk level can also come from your gene for a protein called apo E. The majority of people in the US have zero copies of APOE4. Having 1 copy increases the risk of developing Alzheimer’s around three-fold, and two copies of the APOE4 gene increases risk by around ten-fold. There are several problems with tests for APOE, and it is not necessarily accepted as a useful test to predict AD risk https://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/35358, so your MD may or may not want to order it. Changes in FDA regulations now allow 23andMe to give you your APOE genotype if you buy the “Health and Ancestry Service” https://www.23andme.com/dna-reports-list/. DashGenomics https://www.dashgenomics.com/ has their own proprietary analysis of the genetic data you get from 23andMe or Ancestry.com (Desikan et al., 2017), and they will provide you with a risk score, but again, this is not a validated clinical test. Researchers are actively trying to nail down more about the contribution of specific genes to AD and the more volunteers they have to provide clinical data the better https://www.nia.nih.gov/health/alzheimers-disease-genetics-fact-sheet#testing. People with cognitive impairment can discuss with their neurologist which genetic tests they think will be useful.

With the limited treatment options at this point, if cognitive impairment is suspected or diagnosed, it may be more important to support the health of brain cells in whatever ways you can than it is to nail down the exact chemistry in your brain. When recruiting subjects for research on early stages of Alzheimer’s disease, subjects are tested for mild cognitive impairment—whether or not they have AD or some other form of dementia is frequently not known. This means that we don’t really have specific treatments or lifestyle options tailored to specific types of dementia. An exception to this may be when the brain isn’t getting enough blood because of unhealthy blood vessels. We do know quite a bit about improving cardiovascular health.

OPTIMIZE YOUR LIFESTYLE TO HELP YOUR BRAIN DO ITS BEST

Help neurons survive in a hostile world with whole foods and exercise and meditation. Get treatment for sleep apnea, high blood pressure, high cholesterol, high blood sugar. We may not yet have magic bullets to zap amyloid plaque, but we can provide neurons with the oxygen, fuel, and nutrients they need to function as optimally as possible. Both medical treatments and lifestyle optimization can make a huge difference. First, it’s important to obtain medical treatment for hearing loss, for depression, and for any condition that deprives the brain of blood, oxygen and nutrients, such as sleep apnea and cardiovascular disease. Second, implementing a healthy lifestyle is essential not only for getting neurons the fuels, oxygen, and nutrients they need, but also for minimizing neuronal stressors. The lifestyle suggestions below will probably not be new to you, but maybe the realization that they can help keep your brain functioning will finally motivate you to act. The studies discussed below provide evidence that your brain will benefit when you stop smoking, eat whole foods, get plenty of sleep, get plenty of physical exercise, exercise your brain regularly, and find ways to deal with the stressful demands in your life. A 2017 Lancet report concluded that 35% of dementia possibly could be preventable by modifying key risk factors: obesity and hypertension, physical inactivity, diabetes, smoking, hearing loss, social isolation, depression, and low education (Livingston et al., 2017).

Give um the finger

The FINGER trial (Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability) was the first large, long-term randomized, controlled trial to show that lifestyle intervention can benefit cognition. Cognition refers to acquiring knowledge, understanding, thinking, learning, and memory. Subjects at risk of developing dementia underwent a lifestyle program focused on nutrition, physical activity, cognitive training, and on keeping blood vessels healthy through management of high blood pressure, cholesterol, and blood sugar. After 2 years, the intervention group scored significantly better than the control group on a battery of tests (Ngandu et al., 2015) (Rosenberg et al., 2018). The nutrition recommendations were not drastic, just standard government recommendations for more veggies and fruits, etc.(Becker et al., 2004) and https://www.evira.fi/en/foodstuff/healthy-diet/the-plate-model2/. Physiotherapists led sessions focusing on muscle strength and aerobic activities. Group discussions and computer training modules focused on memory and mental speed. This trial did not include subjects with Alzheimer’s, but the subjects were chosen because they were judged at a higher than average risk of dementia for a variety of reasons. Other lifestyle intervention trials have not demonstrated benefits for cognition, perhaps because the subjects weren’t high risk—maybe they were too healthy to benefit? The FINGER trial has provided evidence that the usual lifestyle suspects are important for maintaining brain function as we age.

nutrient rich diet

A nutrient rich diet means whole foods, not processed foods. Give your brain the vitamins and minerals it needs. That muffin you had for breakfast means your brain was deprived of the magnesium and potassium and B vitamins that were removed when wheat and sugar cane were turned into flour and sugar. Nutrients that are especially important for brain function include magnesium, B-vitamins, lutein, and zeaxanthin—and the best sources of these are plant foods, e.g. vegetables. There is one B vitamin that is not found in plant foods and that is extremely important for neuronal health—vitamin B12. It can take years to deplete the body of this unusual vitamin, so vegans may feel they are fine without meat or supplements until irreversible damage occurs. Dairy and eggs have some B12, but you need to eat a fair amount, so vegetarians will also benefit from supplements. Over 50? There is a good chance you aren’t absorbing B12 as well as you used to—definitely not if you use antacids. Even the US Food and Nutrition Board, which is quite conservative, has recommended that everyone over the age of 50 take a B12 supplement. Despite claims to the contrary, there really isn’t evidence that one type of B12 supplement is better than another. The brain and eyes are where the long omega-3 fats (DHA, EPA) are most concentrated in the body, reflecting their essential roles in vision and neuronal function. Everyone knows that you get DHA and EPA from seafood, but not very well publicized is the fact that meat and eggs, especially grass-fed, are significant sources. Your body can make DHA and EPA from the short omega-3 fat (alpha-linolenic acid, ALA) in flax, walnuts, soy, and canola (Welch et al., 2010). For some reason flax and walnut oils are perceived as healthier than soy and canola oils, but they are all good sources of omega-3’s. Just be sure to refridgerate oils, nuts, and seeds, other than olive oil and coconut oil, to keep the omega-3’s from turning into damaging oxidized fats.

Physical Activity

People who are physically active are less likely to get Alzheimer’s. This would appear to be a no-brainer (sorry), because physical activity can improve blood flow to the brain and increase production of BDNF and other factors that are neuroprotective (Chieffi et al., 2017). It isn’t clear that exercise alone is a magic bullet – even though a meta-analysis of controlled studies concluded that there are significant benefits of aerobic exercise (Groot et al., 2016), not everyone is convinced (National Academies of Sciences, Engineering, and Medicine et al., 2017). It’s worth highlighting Dr. Ozioma Okonkwo’s research to drive home how important physical activity can be for the brain. “When I looked at the data, the findings were unbelievable. I mean, I could not make this up if I wanted” said Okonkwo of his 2014 study findings (Okonkwo et al., 2014)(Chin and Okonkwo, 2017). Middle aged people who were physically active had less age-related brain shrinkage and less age-related memory loss than people with an inactive lifestyle. Brain shrinkage—it really happens with aging and it is measurable. It could have been a coincidence that active people also had healthier brains, but the connection is worth taking seriously.

Stress

You’ve heard about the benefits of reducing stress ad nauseum. Too much cortisol is not good for your brain, especially for the memory-containing hippocampus, so most practitioners recommend minimizing stress, or at least developing strategies to handle stress better, such as meditation or yoga. In a primate model of stress-induced depression, researchers observe not only increased cortisol, but also smaller volume of the hippocampus–as is seen in AD (Schuff et al., 2009) (Sapolsky, 2001). Dr. Robert Sapolsky is well known for studying what goes on when humans and zebras and baboons experience stress (one of his most well-known books is “Why Zebras Don’t Get Ulcers” https://www.goodreads.com/book/show/327.Why_Zebras_Don_t_Get_Ulcers). His research team at Stanford University has shown that too much cortisol (the animal equivalent) too often or for too long is especially damaging to the hippocampus and to memory by increasing inflammation and oxidation. When hippocampal neurons are experiencing low oxygen from clogged blood vessels or from sleep apnea, or are subjected to low blood sugar, what can push them over the edge and kill them is the additional presence of cortisol, the stress hormone (Sorrells et al., 2014)(Dumas et al., 2010).

What can you do about stress? Ashwagandha and holy basil are two adaptogenic herbs from the Ayurvedic tradition that are used to help the body deal with stress and anxiety. Since stress results in all sorts of physical manifestations, it’s not surprising that research has demonstrated a variety of benefits from ashwagandha not only for lowering cortisol levels, stress and anxiety (Chandrasekhar et al., 2012), but also for energy levels, fertility (Nasimi Doost Azgomi et al., 2018), sexual health, and libido (Dongre et al., 2015), and of most relevance here, for memory and cognition (Chengappa et al., 2013). Benefits of holy basil have been demonstrated clinically for forgetfulness and for sleep problems (Saxena et al., 2012) (Jamshidi and Cohen, 2017). Because of the relationships between stress, sleep and cognition it makes sense that adaptogenic herbs could have benefits for all three concerns. As always with dietary or herbal supplements don’t go for the least expensive option. Make sure they are tested for heavy metals and manufactured in GMP facilities. The larger and more well-known manufacturers are most likely to have comprehensive safety and testing programs.

Fuel your brain cells

Keep your blood vessels clear so blood can reach brain cells with vitamins, oxygen, glucose, and ketone bodies. Stroke, when circulation to part of the brain fails, and vascular disease, even partial blockage of blood vessels, are major causes of cognitive impairment. If you are at risk of cardiovascular disease from high blood cholesterol, high blood sugar, high blood pressure, or other factors, do some serious consultation and remediation together with your health care team. Plant sterols, including beta-sitosterol, and psyllium husk are supplements proven to reduce blood cholesterol levels (Law, 2000) (Wei et al., 2009). Further recommendations for keeping your blood vessels healthy can be found in the gooPhD article on Heart Disease (LINK). Diabetes is also very damaging to blood vessels and needs to be well managed, and further information can be found in the gooPhD article on Diabetes (LINK).

Sleep is healing

There is lots of evidence that chronically disrupted sleep, whether from sleep apnea or other causes, increases the risk of developing Alzheimer’s. People with AD tend to wake frequently at night and to spend more time in bed during the daytime but the significance of poor sleep regulation goes way beyond these behaviors (Vanderheyden et al., 2018). Increased amyloid beta levels can result merely from disruption of sleep. Since amyloid beta levels go down overnight it appears that cleansing processes are revved up during sleep. Similar to the lymphatic system in the body, a new cleansing process for the brain has been dubbed the glymphatic. In the glymphatic system glial cells and cerebrospinal fluid remove substances like amyloid, and this cleansing flow increases and is more efficient at night, at least in preclinical research (Cedernaes et al., 2017). Exactly why sleep is so important is not completely understood, but it would appear very worthwhile addressing any sleep problems.

Progesterone and Melatonin for sleep

Difficulties sleeping increase as we age, and this is a particular concern for women during menopause. This may be linked to a drop in progesterone levels, and progesterone supplements may be helpful (Schüssler et al., 2018). Bioidentical progesterone is available by prescription and as an over the counter cream. Estrogen therapy can reduce hot flashes and night sweats that make it difficult to sleep. However, from the discussion in the next section, you can see that it’s not clear whether estrogen hormone replacement therapy (HRT) is indicated in AD—the benefits and risks need to be weighed for each individual. Melatonin supplements are an obvious possibility—it is a very effective sleep aid and as a bonus it possesses antioxidant and neuroprotective effects that are being studied for benefits in AD (Balmik and Chinnathambi, 2018)(Shi et al., 2018). In animal models, melatonin can help with amyloid beta clearance and there is even evidence that it can decrease amyloid plaque formation (Pappolla et al., 1998). Results in animal models frequently do not translate to humans, but even if melatonin does not turn out to be an anti-AD drug, it is looking like a very good option for help sleeping. Always start with a low dose of melatonin, around 1 mg, to see how that works, and if necessary, increase the dose. It’s been shown to be quite safe at much higher levels but for some people too much causes unpleasant dreams.

Deal with sleep apnea

(Does your partner snort and gasp at night?). One cause of disrupted sleep that is clearly associated with cognitive impairment, and likely even with Alzheimer’s, is sleep apnea (Andrade et al., 2018). If you’ve ever laid in bed listening to your partner breathing, and realized at some point that they’ve stopped breathing, it probably occurred to you that their brain was not getting oxygen, which is a frightening thought. It seems obvious that cessation of breathing, referred to as sleep apnea, would have undesirable consequences including low oxygen levels in the brain. In the most common type of sleep apnea, an obstruction in the upper airway causes breathing to stop for a few seconds to a few minutes and this can happen multiple times every hour. When breathing resumes, you may hear snoring and gasping and snorting. Remedies you can try on your own include drinking less alcohol, which relaxes throat muscles that can then close the airway, and not smoking to reduce airway inflammation and swelling. Diagnosis, which may include a sleep study, commonly leads to being prescribed a CPAP (positive airway pressure) machine that essentially blows air to keep your airways open https://www.nhlbi.nih.gov/health-topics/sleep-apnea#Signs,-Symptoms,-and-Complications.

CONVENTIONAL TREATMENTS- WHAT DOES YOUR DOCTOR HAVE IN HER ARSENAL?

Topline for drugs

FDA approved drugs don’t cure Alzheimer’s but they can help with memory loss and confusion and provide significant benefits for a year or more. The bad news is that there are currently no drugs that delay or prevent the death of neurons in AD. The good news is that there are several FDA approved drugs that can help temporarily with memory loss and confusion—https://www.alz.org/alzheimers-dementia/treatments/medications-for-memory. Cholinesterase inhibitor drugs (Aricept (donepezil), Exelon (rivastigmine), Razadyne (galantamine)) can help maintain the level of the neurotransmitter acetylcholine in the brain and delay or slow worsening of symptoms. Memantine (Namenda, or Namzaric when combined with donepezil) affects a different neurotransmitter, glutamate, and can improve ability to perform daily activities and improve mental function. These drugs do not treat the underlying disease or slow its progression, but they can improve symptoms by supporting the brain cells that are still alive. The result is that the remaining supercharged neurons can help the brain function more normally. If you look online you’ll find people posting positive and negative reviews of these drugs. Anecdotes and clinical studies have shown that in some cases these drugs can provide a meaningful amount of higher quality time. As with most drugs, these do have side effects. For the cholinesterase drugs side effects may include nausea, vomiting, loss of appetite and increased frequency of bowel movements, and for Memantine side effects can be headache, constipation, confusion and dizziness. Benefits and side effects should be discussed with your medical practitioner and monitored.

Topline for hormone therapy

Use bioidentical estrogen only if the benefits outweigh the risks for you. Researchers keep trying to find evidence that hormone replacement therapy (HRT) with estrogen has benefits for cognition during menopause. As of yet they have not. In fact, studies to date have shown that HRT is not good for the brain (Henderson, 2014). The most damning results have come from the Women’s Health Initiative that utilized equine estrogen with or without medroxyprogesterone in women over 65 years of age (Shumaker et al., 2004). Earlier in menopause HRT appears to be less harmful, and bioidentical 17-beta estradiol may be less harmful than equine estrogen (Kantarci et al., 2016). In the absence of a benefit, and with the possibility of detrimental effects on the brain, it would not seem advisable for women concerned about cognition to use HRT for extended periods of time. For a more thorough discussion of this see the Menopause article in this series (LINK).

ALTERNATIVE TREATMENTS- WHAT MIGHT YOU WANT TO CHECK OUT?

Topline for alternative approaches. Read The End of Alzheimer’s. Turmeric (curcumin) and bacopa are my topline botanical recommendations. Ketogenic diets are hot.

Dr. Bredesen and ReCODE.

Dr. Dale Bredesen is the president and CEO of the Buck Institute for Research on Aging in Novato, and the director of UCLA’s Alzheimer’s Disease Research Center. His lab studies neurodegeneration in AD and applies findings to develop treatments. Dr. Bredesen’s new book, The End of Alzheimer’s: The First Program to Prevent and Reverse Cognitive Decline describes the protocol used in the first documented cases to reverse and stop the progression of AD (Bredesen et al., 2016). Improvements were actually reported in patients with documented Alzheimer’s disease with a treatment protocol they call the ReCODE (formerly MEND) protocol. Nine of 10 patients with Alzheimer’s or other cognitive impairment showed improvements- either in test scores or subjective ratings, and some were able to return to work. The results from the very small pilot study have been described in two research articles (Bredesen, 2017, 2014; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4221920/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4931830/). The approach is holistic, intensive, and demanding, and uses a three-pronged approach to help keep neurons alive: reduce inflammation, provide nutrition to brain cells, and reduce toxic insults to brain cells (i.e. heavy metals and stress hormones). Some of the more interesting components are fasting at least 12 hours nightly, carefully controlling levels of insulin, cortisol and other hormones, and avoiding gluten. He prescribes an array of supplements unusual for a medical doctor: ashwagandha, bacopa, turmeric, vitamins D3 and K2, resveratrol, citicoline, and much more. Some of the more common stress- and inflammation-reducing components include minimizing simple carb intake, and getting plenty of sleep, exercise, yoga, meditation, and music. Note that this research consists of case studies—there weren’t untreated control subjects to compare the results to—so these results are considered preliminary. Also, Dr. Bredesen is candid about the fact that he only treats highly motivated patients due to the difficulty of following the protocol. As with all small pilot studies, the results may not be replicated when a larger and controlled study is carried out, but this approach is pretty intriguing. Dr. Bredesen has trained a large number of practitioners to carry out the ReCODE protocol—it is not something that could be carried out without collaboration with a health care practitioner. Look for information about participating at https://www.drbredesen.com/mpicognition. v

Supplements- botanicals

The most promising supplements for cognitive benefits are botanicals, which is no doubt why Dr. Bredesen includes them in his protocol. Plants used traditionally in Ayurveda to slow brain aging include brahmi (Bacopa monnieri), turmeric, gotu kola (Centella asiatica), ashwagandha (Withania somnifera; discussed above), and other herbs and combinations. Gotu kola has been used in traditional Chinese medicine as well as in Ayurveda to improve mental clarity, and there is evidence from animal and clinical studies that it can provide benefits for mood and memory (Farooqui et al., 2018; Orhan, 2012), however benefits have not been demonstrated clinically for any type of dementia.

Brahmi

Brahmi (Bacopa monnieri) is one of the better-studied and more effective herbs for cognitive support. A number of (but not all) double-blind, placebo-controlled studies showed that healthy older adults given bacopa for as little as 4 weeks performed significantly better on tests of memory, attention, and cognitive processing (Peth-Nui et al., 2012) (Calabrese et al., 2008)(Raghav et al., 2006)(Morgan and Stevens, 2010)(Nathan et al., 2001; Stough et al., 2008). So bacopa appears to be effective in healthy adults but we are still waiting for evidence that it helps people with mild cognitive impairment or AD.

Turmeric/curcumin

If turmeric was protective, you might expect that regularly eating curry with turmeric (e.g. in Indian culture) might be linked to less AD and to better cognition, and indeed that argument has been made. In addition, animal research has shown that the active component in turmeric, curcumin—with anti-inflammatory and antioxidative effects—does have benefits for survival of neurons and reduces plaque and tangles. Breakthrough clinical research published in 2018 by Dr. Gary Small and others at the Brain Research Institute, UCLA, has now shown that not only can curcumin improve memory, attention and mood, but that it can also lower the amounts of plaques and tangles in the hypothalamus. Subjects were given a high dose of a uniquely bioavailable form of curcumin, Theracurmin® (90 mg curcumin twice daily) for 18 months (Nathan et al., 2001). Since 40% of the subjects in this study were classified with mild cognitive impairment, Theracurmin’s benefits may be relevant for AD, but as with bacopa, definitive studies on subjects with actual AD have not yet been carried out.

Other vitamin etc. supplements

A recent review of 38 trials found that more evidence was needed as to whether any of the following supplements by themselves can reduce cognitive decline: omega-3 fatty acids, soy, folic acid, beta carotene, vitamin C, vitamin D plus calcium, and multivitamins or multi-ingredient supplements (Butler et al., 2018). There has been a lot of talk about Ginkgo biloba and cognitive improvement, but research has not shown that it does a lot on its own. In the Ginkgo Evaluation of Memory Study, 3,000 participants aged 75 and older took daily ginkgo. Results showed that the supplement did not reduce risk of dementia, including AD, and did not slow cognitive decline (DeKosky et al., 2008). Just because these supplements can’t individually cure dementia does not mean that getting optimal levels of all nutrients isn’t important in supporting your brain.

Drink coffee

Coffee and caffeine are some of the best studied short-term treatments to improve performance on all sorts of tests of memory and learning, so it makes sense that caffeine could be helpful for cognitive impairment in the long term. Looking at large populations and correlating the amount of coffee or tea they drink with whether or not they develop AD, most studies have found that moderate caffeine intake appears to go hand in hand with less AD (Wierzejska, 2017)(Hussain et al., 2018). Conclusion: drink coffee if you like it, but not so much that you are anxious or don’t sleep well.

Ketogenic diets are hot- read this

The number of ongoing clinical trials on ketogenic diets reflects the building evidence that these diets can improve cognition in people with Alzheimer’s by providing the brain with ketone bodies, a fuel alternative to glucose. More and more research points to brain cells not getting the fuel they need in AD—and they do need much more fuel relative to their weight than most of the body. Glucose is the usual fuel for brain cells, but for poorly understood reasons in AD less glucose gets into the brain and less is burned as fuel. Ketone bodies, on the other hand, readily enter the brain and neurons love to use them as fuel.

Ketone bodies are made in the liver from fats, and most of the body is happy to use them for energy. They’ve gotten a bad rap at times because too high a level (ketoacidosis) is not healthy, but moderate levels are beneficial. There are many versions of ketogenic diets, all of which limit carbohydrates and increase fat. Fat consumption is increased because they can be made into ketone bodies, but the liver won’t do this unless there isn’t much glucose around. Dietary carbs including sugar, starch, fruits, bread, and pasta, are limited because they are all broken down during digestion to yield glucose, which will prevent ketone body production.

An extreme version of a ketogenic diet would consist of mostly fat with very little of carb plus protein. Protein can be made into glucose, so it is limited also. There are safer and more moderate versions recommending 1-2 grams of fat for every gram of protein plus carb eaten. A relatively recent version of a ketogenic diet uses a unique type of fat, medium chain triglycerides (MCT), which promotes ketone body production and requires eating less fat (Pinto et al., 2018). What’s unique about MCT is the types of fatty acids, which are shorter than those in most foods. Coconut oil and palm kernel oil and dairy contain a little of these short fats, but to make MCT the short fats are purified and concentrated, so it’s quite different from coconut oil. MCT is a vague term—unless the label specifies, you don’t really know how much of the desirable short fat, caprylic acid, is in the product.

Axona® is an MCT that is a medical food regulated by the FDA and available by prescription, in which 95% of the fat is caprylic acid. It is made from glycerin from vegetable oil and fats from coconut and palm kernel oils (https://www.alz.org/alzheimers-dementia/treatments/alternative-treatments; Galvin, 2013). This product was actually tested in subjects with mild to moderate Alzheimer’s disease to see if it would affect cognition and daily function. Subjects given around 50 g of Axona every day scored significantly better than placebo-treated subjects on some of the tests of cognition and function (Henderson et al., 2009). The effect was greatest in subjects without the APOE4 gene.

Since then there have been quite a few studies, mostly quite small, that have reported positive effects of MCT on cognition, and it’s interesting that the effects have been seen only in people without APOE4 (Pinto et al., 2018). A recent small study showed that 1.5-3 tablespoons daily of NOW Foods MCT oil as part of a high fat, low carb diet for 3 months resulted in improved test scores in people with clinical dementia (Taylor et al., 2017). The most intriguing results are from 2 small studies that reported improved cognition scores shortly after a single meal of MCTs, and from a study that reported benefits from a more conventional ketogenic diet (Krikorian et al., 2012). As of August 2018, studies at Johns Hopkins, Wake Forest University, Universite de Sherbrooke and the University of British Columbia were still recruiting subjects for studies of ketogenic diets/MCT in subjects with cognitive impairment or AD (https://clinicaltrials.gov/ct2/show/NCT02521818; https://clinicaltrials.gov/ct2/show/NCT03472664; https://clinicaltrials.gov/ct2/show/NCT02709356; https://clinicaltrials.gov/ct2/show/NCT02912936. Note: ketogenic diets and supplements are not without side effects including diarrhea, constipation, nausea, vomiting (McDonald and Cervenka, 2018).

Simulated environments

Does someone with AD want to be reminded of her diagnosis? Patients generally want to hear the truth. How does this play out in AD, when this may require telling your mother over and over again that you are divorced—making her very sad. When she repeatedly asks how your husband is doing you may want to change your answer to “fine”. In “The Comforting Fictions of Dementia Care” (The New Yorker, 10/1/18) Larissa MacFarquhar describes a memory care unit in Ohio that looks like a town from the residents’ childhood, complete with a town square and rocking chairs. To take it one level further, when a resident says “I want to go home”, they might be led to a bus stop where they can wait until they have forgotten why they are there. Fantasies to sooth the uncertainty, fear, and anger of those suffering from dementia can be very kind, although it isn’t necessarily the best approach for everyone.

Simulated presence therapy

Talking with someone familiar is usually very comforting for someone with dementia, and the conversation is frequently pretty repetitive and predictable. It’s easy to imagine that it could be helpful for a loved one to record the usual questions, reassurances, and descriptions of shared experiences and to have this recording available for their family member with dementia to listen to or to watch. If the person is in distress or agitated, it’s thought that such tapes could be useful therapy. There isn’t clear evidence that simulated presence therapy is in fact therapeutic (Abraha et al, 2017), but it certainly seems worth keeping in mind and utilizing when helpful. Companies that help produce these sorts of media may call it trusted voice therapy.

DOES THE LATEST RESEARCH YIELD ANY TANTALIZING INSIGHTS?

Nourishing brain synapses

It seems worthwhile making sure that the brain is provided with nutrients to support healthy neurons and synapses. When subjects with mild Alzheimer’s disease were given a supplement called Souvenaid (Fortasyn Connect®) for only 24 weeks, they scored better on memory tests than control subjects (Scheltens et al., 2012). More recently, comparing patients with mild cognitive impairment who used Souvenaid for one year to patients who chose not to use it, Souvenaid was associated with better results on tests of memory. Souvenaid was also associated with better PET scan results—brain metabolism worsened over a year in control subjects but not in those taking the supplement (Manzano Palomo et al., 2019). However, patients in both groups progressed to full-blown dementia at the same rate. These were small studies and the results are not definitive, but it makes sense that nutrients needed for neurons could be helpful. Souvenaid contains the omega-3 fats DHA and EPA, phospholipids, choline, uridine monophosphate, vitamin E, selenium, vitamin B12, vitamin B6, and folic acid.

Gentle sound stimulation

Our brains consolidate memories while we sleep, specifically during slow-wave sleep. In people with cognitive impairment, there is less slow-wave activity in the brain. When researchers used specific sound stimulation overnight, not only could they increase the amount of slow-wave sleep, but performance was better on a word recall memory test in the morning. And this was after only one night (Papalambros et al., 2019).

Squeezing the brain’s blood supply

In the Alternative Treatments section above, I discussed the value of ketogenic diets in Alzheimer’s, because of the evidence that brain cells may not be getting enough of their usual fuel, glucose, and because brain cells love ketone bodies. It’s known that one reason brain cells may not be getting enough fuel is that blood flow to the brain is reduced in AD– this is one of the earliest changes seen in the brain during the course of disease progression. Researchers at University College, London have discovered a reason for restricted blood flow—they’ve shown that amyloid beta can cause the cells surrounding capillaries to contract and to squeeze the vessels, narrowing them (Nortley et al, 2019).

Microbial infections

The most interesting research I’ve seen to date has to do with the possibility that infections by viruses, bacteria, and fungi contribute to Alzheimer’s. The brain could be making amyloid beta peptide because it is trying to fight off an infection—amyloid beta has actually been shown to be antimicrobial (Soscia et al., 2010). That would explain why multiple types of infections, discussed below, have been linked to Alzheimer’s—amyloid beta may be a general defense mechanism.

Fungal infections

Some very clear-cut data have been published that show multiple types of fungi in brains of Alzheimer’s patients, with none detected in brains of control patients. Candida albicans and Sacharomyces cerevisiae and other species have been shown to be present in various brain regions affected in Alzheimer’s by DNA analysis and by other techniques. Researchers hypothesize that fungal infections could either be a cause of or at least contribute to the disease (Pisa et al., 2015). Amyloid beta peptide is not only antimicrobial, but it may be particularly potent against the fungus C. albicans. It’s intriguing that fungal infection can be misdiagnosed as Alzheimer’s and treated successfully with anti-fungal drugs (Hoffmann et al., 2009). In one case an Alzheimer’s-like dementia cleared up with treatment for Cryptococcal meningitis, a serious infection of the brain caused by a common fungus found in soil and in bird droppings (Ala, Doss, and Sullivan, 2004). Were these cases of misdiagnosis after all?

Herpes infection.

Super intriguing—could the herpes virus helps predispose the brain to Alzheimer’s? The herpes variant best studied in this way is HSV-1, the herpes commonly associated with cold sores. The HSV-6a and HSV-7 viruses that cause roseola rash in kids have also been implicated—they are often found in the brains of people who had AD (Readhead et al., 2018; https://www.ncbi.nlm.nih.gov/pubmed/2993727). There is no proof that herpes causes Alzheimer’s and the viruses are found in healthy brains also, but there is evidence that they commonly occur together, particularly in people with the APOE4 gene. Herpes viruses can lay dormant in cells for years, and can be reactivated by stress, immunosuppression (or possibly the weakened immune system in aging?), fever, and brain trauma. Reactivated HSV-1, but not lifelong infection, appears to go along with Alzheimer’s (Hogestyn et al., 2018) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5879884/. Could anti-viral drugs be preventative? Dr. Devanand of Columbia University is conducting a blinded, controlled clinical trial to test the “viral hypothesis”. Subjects will be given the HSV drug, valacyclovir, for 18 months. The accumulation of amyloid and of tau in the brain will be measured at the beginning and end of the trial. Enrollment for the study is open as of April 2019 https://clinicaltrials.gov/ct2/show/NCT03282916.

Bacterial infections

The microbes that have been found in AD brains include several kinds of spirochete bacteria (Ranjan et al., 2018). Are they causative? Coincidental? Do microbes gain access to damaged brains? When spirochete bacteria from AD brains are incubated with healthy brain cells in culture, they can cause tangles and plaques and Alzheimer’s like pathology. One of the microbes implicated is the spirochete Borrelia burgdorferi (Miklossy, 2008), which happens to be one of the Borrelia species that causes Lyme disease. This spirochete can cause a dementia called Lyme neuroborreliosis that can be treated with antibiotics. Walking abnormally, gait disturbances, falls, tremor, and a history of tick bites might point toward this particular kind of dementia. It’s interesting to read the case studies of patients with dementia eventually determined to have Lyme disease (Kristoferitsch et al., 2018).

The periodontal pathogen, Treponema pallidum and other Treponema species have also been implicated in Alzheimer’s (Miklossy, 2011). Because chronic periodontitis has been found along with AD, it’s hypothesized that periodontal infections might contribute indirectly through causing inflammation (Harding et al., 2017). Inflammation can increase the susceptibility of neurons to other damaging factors such as amyloid, tau, oxidation, and infection. Practice good dental hygiene but don’t be too enthusiastic because poking the gums can also let bacteria into the blood.

A “$1 million prize will go to the scientist or team providing persuasive evidence…that a particular infectious agent is the cause of most Alzheimer’s disease. The deadline for submissions is December 31, 2020.” This comes from Rainey and Dr. Leslie Norins, who founded Alzheimer’s Germ Quest Inc, a private company with the goal of speeding up research on infectious agents as causes of AD (https://alzgerm.org/about/). I wonder if they will pay out if it is determined that a number of infectious agents can all cause the disease.

Oligomers

Professor Dennis Selkoe’s team at Harvard Medical School thinks that the large plaques of amyloid beta that build up in the brain in Alzheimer’s disease are not the culprits for memory loss—that instead we should blame short chains of amyloid beta that can more easily move around the brain. According to Selkoe, plaque contains millions of copies of amyloid beta, but they aren’t doing a lot of harm there—the problem is when chains of 2 or 3 or 4 amyloid beta peptides, called oligomers, are formed and float into synapses, especially in the hippocampus, the center of memory. His researchers actually took oligomers from the brains of deceased AD patients and injected them into rat brains. Even very tiny amounts caused the animals to become forgetful. What’s most interesting is that the effect was temporary (Yang et al., 2017; Zhao et al., 2018). It’s disappointing that clinical trials using antibodies to amyloid beta have not yielded positive results (Gold, 2017; Honig et al., 2018). Yet another antibody is being tested in a clinical trial, crenezumab–it will target amyloid oligomers (Tariot et al., 2018; https://clinicaltrials.gov/ct2/show/NCT03114657). Therapies designed to block the harmful effects of the oligomers at synapses are no doubt in development. For more immediate use, tests to screen patients for the toxic oligomers are being developed (Hwang et al., 2018).

Anti-inflammatories of various sorts

Non-steroidal anti-inflammatory drugs were in the news a while ago when preliminary research suggested that they might be helpful in Alzheimer’s disease. Drugs in this class include indomethacin, naproxen, aspirin, celecoxib (you might know these by the brand names Indocin, Aleve or Naprosyn, Celebrex). Unfortunately, since then clinical studies on subjects with Alzheimer’s have not shown significant benefits from these drugs (Ardura-Fabregat et al., 2017). This is a good example of why we shouldn’t get too excited by certain kinds of preliminary research—where conclusions are based on correlations. In this case, a correlation was reported between using non-steroidal anti-inflammatory drugs and a lower rate of Alzheimer’s. People who reported taking anti-inflammatories were developing less Alzheimer’s than expected. Correlations of this sort can be misleading—you’ll hear this kind of research referred to as ‘epidemiological’, and while it can be intriguing and suggestive, it is frequently a dead end. Second, animal research looked very positive as far as benefits of these drugs. We learn a lot from animal research, but the majority of the time it leads to dead ends also, possibly due to just not having the animal equivalent of Alzheimer’s disease to study.

Your ability to identify odors

The usual tests to assess how well our brain is working, and whether our cognition is deteriorating, evaluate our memory and our ability to carry out tasks. An interesting new biomarker for brain function is ‘odor detection impairment’–it correlates with brain volume, a well-accepted measure of brain health. The brain shrinks with age and shrinkage is greater in AD. Impaired ability to identify odors appears to be a marker of mild cognitive impairment and of AD (Hagemeier et al., 2016). The hope is that assessing sense of smell could be a simple, noninvasive way to judge how well therapies are working.

CLINICAL TRIALS ARE ALWAYS RECRUITING SUBJECTS

Be a subject in the latest research. Go to https://www.alzforum.org/clinical-trial-registries to find out about ongoing clinical studies that you may participate in. On this site, links to The Alzheimer’s Association TrialMatch and to the Alzheimer’s Prevention Registry can help you find trials you may be eligible for. The Brain Health Registry offers cognitive tests and will notify you if you are eligible for specific clinical trials. Or you can go straight to the National Institutes of Health (NIH) site for clinical trials and search on your own, https://www.nia.nih.gov/research/ongoing-alzheimers-and-related-clinical-trials-and-studies. https://clinicaltrials.gov/ct2/results?cond=Alzheimer+Disease&term=&cntry=&state=&city=&dist=. Clinical trials have been described in other sections of this article. See the sections on ketogenic diets and on herpes.

The POINTER STUDY

The POINTER STUDY will see if a combination of lifestyle modifications—“healthy diet, physical activity, and social and intellectual challenges”—can reduce development of Alzheimers in subjects at risk of this disease. This approach was shown to be beneficial in a Finnish study (FINGER) and was more effective than any drug tried so far. Subjects must be 60-79 y of age and have a close relative with memory impairment.

Stopping AD in the early stages

Dr. Eric Reiman of the Banner Alzheimer’s Institute in Phoenix is leading a large clinical study to see if drugs—injected immunotherapy or an oral drug that can stop formation of amyloid peptide—that have not previously been effective in clinical trials, might be able to prevent AD if treatment is started early enough. In order to do this, subjects have to still be healthy, and in order to make sure they have enough subjects who would otherwise develop AD, the subjects have to be in a very high risk group, in this case people with two copies (homozygous) for the APOE4 gene.

The Tetra Picasso AD Trial

The Tetra Picasso AD Trial wants to to harness the brain’s natural mechanisms for supporting memory, to improve functioning in the presence of amyloid buildup. Under the direction of Dr. Scott Reines, Tetra Discovery partners will evaluate the drug BPN14770 at multiple locations in the US. The hope is that the drug will be able to increase levels of cAMP, a messenger molecule, in the brain, which will then support neuronal function and memory.

Alzheimer’s Treatment With 40 Hz Light

Alzheimer’s may be associated with impairments in gamma brain waves, so Dr. Li-Huei Tsai, director of MIT’s Aging Brain Initiative, asked if inducing gamma waves might be beneficial. It turned out that in mice, exposure to flickering light (40 hertz) not only induced gamma waves but decreased amyloid plaque (Martorell et al., 2019). Sound at 40 hertz could also be used to induce gamma waves, reduce amyloid plaque, and improve cognition. In this clinical study, 40 hertz light will be used together with cognitive therapy, consisting of a program called AlzLife that uses games such as Sudoku and Tic-tac-toe to exercise your brain. Another study is using electrical stimulation at 40 hertz to induce gamma waves in the brains of people with Alzheimer’s.

Nicotine patches

A pilot study by Dr. Paul Newhouse at Vanderbilt University showed that transdermal nicotine patches improved cognitive performance (Newhouse et al., 2012) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3466669/. His team is currently conducting a larger clinical study in patients with mild cognitive impairment. Of course, this is NOT a recommendation to start smoking.

Vitamin D

At UC Davis, Dr. John Olichney is studying whether vitamin D improves cognitive outcomes, since preliminary research has linked low vitamin D with increased risk of dementia and AD (Miller et al., 2015). A clinical study will compare 4000 IU vitamin D (the amount some research has shown may be required to maintain healthy blood levels) to 600 IU in subjects with mild cognitive impairment, mild AD, or healthy cognition.

Misc Drugs

A lot of drugs have been studied in clinical trials. You may have heard of PPAR activating drugs like rosiglitazone and pioglitazone that have been reported promising effects on mild dementia. However the TOMMORROW clinical trial on pioglitazone was just terminated (8/14/18) because of a lack of efficacy. Find out what is being tested currently- there is always something new.

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